Abnormalities of brain structure and function are one of the key neurobiologic characteristics of schizophrenia. In schizophrenia subjects, losses of tissue volume, changes in neuronal density, and deficits of functional activation are present within a circuit of neural structures. The central scientific goals of this Conte Center for the Neuroscience of Mental Disorders (CCNMD) are to more precisely define the anatomical pattern of these abnormalities in brain structure and function, to investigate their possible causes (i.e., genetic and/or environmental) and pathogenesis, and to establish functional links between these structural abnormalities and abnormalities of cognitive function (e.g., working and episodic memory) that may underlie psychopathology and disability. Our overarching hypothesis is that genetic liability for schizophrenia may be expressed in part by variation in neuroanatomical structure and function within a network of specific brain regions and that these same structures may be impacted by environmental insult during early development, ultimately leading to the cognitive and clinical abnormalities that currently define the disease. The proposed CCNMD will 1) carry out an integrated investigation of brain structure and function in schizophrenia subjects, their non-psychotic siblings, healthy controls and their siblings.2) Study the developmental progression of changes in brain structure in a macaque model of fetal environmental insult. and 3) elucidate the specific cellular elements of the neural circuit underlying working memory again using macaques. Finally, we will use recombinant, inbred strains of mice to identify genes that influence these neuroanatomical and behavioral phenotypes. Several themes are carried across the individual Projects proposed for the Center. Taken together with shared technologies and resources, the overarching hypothesis and these themes represent a strong rationale for the funding of this research as a Center, rather than a series of R01 projects. [unreadable]